Targeting AXL induces tumor-intrinsic immunogenic response in tyrosine kinase inhibitor-resistant liver cancer

被引：8

作者：

Xie, Yunong ^{[1
,2
]}

Wu, Haofeng ^{[1
]}

He, Yimiao ^{[1
]}

Liu, Linglin ^{[1
]}

Huang, Ianto Bosheng ^{[2
]}

Zhou, Lei ^{[2
,3
]}

Lin, Cheuk-Yin ^{[2
]}

Leung, Rainbow Wing-Hei ^{[4
]}

Loh, Jia-Jian ^{[2
]}

Lee, Terence Kin-Wah ^{[4
]}

Ding, Jin ^{[5
]}

Man, Kwan ^{[6
,7
]}

Ma, Stephanie ^{[2
,7
,8
]}

Tong, Man ^{[1
,2
]}

机构：

[1] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Peoples R China

[2] Univ Hong Kong, Li Ka Shing Fac Med, Sch Biomed Sci, Hong Kong, Peoples R China

[3] Sun Yat Sen Univ, Affiliated Hosp 1, Precis Med Inst, Guangzhou, Peoples R China

[4] Hong Kong Polytech Univ, Dept Appl Biol & Chem Technol, Hong Kong, Peoples R China

[5] Naval Med Univ, Clin Canc Inst, Ctr Translat Med, Shanghai, Peoples R China

[6] Univ Hong Kong, Li Ka Shing Fac Med, Sch Clin Med, Dept Surg, Hong Kong, Peoples R China

[7] Univ Hong Kong, State Key Lab Liver Res, Hong Kong, Peoples R China

[8] Univ Hong Kong, Shenzhen Hosp, Shenzhen, Peoples R China

来源：

CELL DEATH & DISEASE | 2024年 / 15卷 / 02期

关键词：

NECROSIS-FACTOR-ALPHA; CELL-DEATH; SORAFENIB; CABOZANTINIB; ACTIVATION; SUNITINIB; NIVOLUMAB; BLOCKADE; GROWTH;

D O I：

10.1038/s41419-024-06493-0

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Hepatocellular carcinoma (HCC) is an aggressive malignancy without effective therapeutic approaches. Here, we evaluate the tumor-intrinsic mechanisms that attenuate the efficacy of immune checkpoint inhibitor (ICI) that is observed in patients with advanced HCC who progress on first-line tyrosine kinase inhibitor (TKI) therapy. Upregulation of AXL observed in sorafenib- and lenvatinib-resistant HCCs is correlated with poor response towards TKI and ICI treatments. AXL upregulation protects sorafenib-resistant HCC cells from oxidative stress, mitochondrial damage, and accompanying immunogenic cell death through suppressed tumor necrosis factor-alpha (TNF-alpha) and STING-type I interferon pathways. Pharmacological inhibition of AXL abrogates the protective effect and re-sensitizes TKI-resistant HCC tumors to anti-PD-1 treatment. We suggest that targeting AXL in combination with anti-PD-1 may provide an alternative treatment scheme for HCC patients who progress on TKI treatment.

引用

页数：15

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